LTBP COMPLEX-SPECIFIC INHIBITORS OF TGFb1 AND USES THEREOF

Abstract

The invention provides method of treating fibrosis, comprising the steps of (a) selecting a TGFβ inhibitor for the treatment of fibrosis, (1) wherein the TGFβ inhibitor (A) specifically binds a LTBP1-proTGFβ complex; (B) does not bind a human GARP-proTGFβ complex; (C) does not bind a human LRRC33-proTGFp complex; and (D) does not bind mature TGFβ1, mature TGFβ2 or mature TGFβ3; and (2) wherein the TGFβ inhibitor is selected using an assay to measure the amount of a marker, wherein the amount of the marker is indicative of the treatment of fibrosis, with the proviso that the marker is not pSmad2; and (b) providing the selected TGFβ inhibitor for administration to a subject in need of treatment for fibrosis. These selected TGFβ inhibitor are isoform-specific, context-selective inhibitors of TGFβ1 that selectively target matrix-associated TGFβ1 activation but not immune cell-associated TGFβ1 activation.

What is claimed is: 
     
         1 . A LTBP-selective TGFβ1 inhibitor for use in the treatment of an inflammatory fibrotic disease in a subject, wherein the treatment comprises administration of an effective amount of a LTBP-selective TGFβ1 inhibitor to the subject, wherein the LTBP-selective TGFβ1 inhibitor is:
 a) an antibody or antigen-binding fragment thereof comprising the following six CDRs: (1) CDR-H1 comprising the amino acid sequence FTFRSYVMH (SEQ ID NO: 1); (2) CDR-H2 comprising the amino acid sequence VISHEGSLKYYADSVKG (SEQ ID NO: 2); (3) CDR-H3 comprising the amino acid sequence ARPRIAARRGGFGY (SEQ ID NO: 3); (4) CDR-L1 comprising the amino acid sequence TRSSGNIDNNYVQ (SEQ ID NO: 4); (5) CDR-L2 comprising the amino acid sequence EDNQRPS (SEQ ID NO: 5); and (6) CDR-L3 comprising the amino acid sequence QSYDYDTQGVV (SEQ ID NO: 6); 
 b) an antibody that is not Ab42 and comprises a VH and a VL each of which has at least 90% sequence identity to SEQ ID NO: 7 and SEQ ID NO: 8, respectively, and binds human LTBP1-proTGFβ1 and human LTBP3-proTGFβ1 with a K D  of 10 nM or less as measured by a surface plasmon resonance (SPR)-based assay (such as BIACORE); 
 c) an antibody that is not Ab42 and competes for antigen binding with SR42 and binds an epitope comprising one or more amino acid residues of the sequence DMELVKRKRIEAIR (SEQ ID NO: 46), wherein optionally the antibody contacts one or more of the residues: Asp27 (D); Leu30 (L); Arg33 (R); Ile36 (I); Glu37 (E); or, 
 d) an antibody that is not Ab42 and competes for antigen binding with SR42 and binds an epitope comprising one or more amino acid residues of the sequence YIDFRKDLGWK (SEQ ID NO: 93), wherein optionally the antibody contacts one or more of the residues: Tyr289 (Y); Lys294 (K); Asp295 (D); 
 wherein the antibody binds recombinant human LTBP1-proTGFβ1 and/or recombinant human LTBP3-proTGFβ1 with at least 50-fold greater affinities over recombinant human GARP-proTGFβ1 as measured in an in vitro binding assay. 
 
     
     
         2 . The LTBP-selective TGFβ1 inhibitor for use according to  claim 1 , wherein the inflammatory fibrotic disease is a viral infection, wherein optionally the viral infection is a severe acute respiratory syndrome; wherein further optionally the severe acute respiratory syndrome is SARS-CoV (e.g., SARS-CoV1) or COVID19 (SARS-CoV2). 
     
     
         3 . The LTBP-selective TGFβ1 inhibitor for use according to  claim 1 , wherein the inflammatory fibrotic disease is a chronic kidney disease (CKD), a chronic lung disease, a chronic liver disease, diabetes, muscle disease, systemic sclerosis, cancer, and/or genotoxic therapy-induced inflammation. 
     
     
         4 . The LTBP-selective TGFβ1 inhibitor for use according to  claim 3 , wherein the chronic kidney disease is diabetic nephropathy, renal fibrosis, and/or Alport syndrome. 
     
     
         5 . The LTBP-selective TGFβ1 inhibitor for use according to  claim 3 , wherein the chronic liver disease is non-alcoholic fatty liver disease (NAFLD), e.g., non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), which may include: noncirrhotic NASH with liver fibrosis, liver cirrhosis, NASH with compensated cirrhosis, NASH with decompensated cirrhosis, liver inflammation with fibrosis, liver inflammation without fibrosis; stage 2 and 3 liver fibrosis, stage 4 fibrosis (NASH cirrhosis or cirrhotic NASH with fibrosis), primary biliary cholangitis (PBC) (formerly known as primary biliary cirrhosis), and/or primary sclerosing cholangitis (PSC), wherein optionally the subject has or is at risk of developing obesity, metabolic syndrome, and/or type 2 diabetes. 
     
     
         6 . The LTBP-selective TGFβ1 inhibitor for use according to  claim 5 , wherein the LTBP-selective TGFβ1 inhibitor is used in conjunction with another therapy comprising a myostatin inhibitor and/or a GLP-1 receptor agonist. 
     
     
         7 . The LTBP-selective TGFβ1 inhibitor for use according to  claim 6 , wherein the myostatin inhibitor is a myostatin-selective inhibitor, wherein optionally the myostatin-selective inhibitor is apitegromab, GYM329, trevogromab, or a variant thereof. 
     
     
         8 . The LTBP-selective TGFβ1 inhibitor for use according to  claim 6 , wherein the myostatin inhibitor is a non-selective myostatin inhibitor, wherein optionally the non-selective myostatin inhibitor is an antibody that binds ActRII (e.g., bimagromab), a ligand trap, or an anti-myostatin Adnectin (e.g., BMS-986089. 
     
     
         9 . The LTBP-selective TGFβ1 inhibitor for use according to  claim 3 , wherein the diabetes is type 1 diabetes or type 2 diabetes. 
     
     
         10 . The LTBP-selective TGFβ1 inhibitor for use according to  claim 3 , wherein the chronic lung disease is IPF, infection, and/or radiation-induced pulmonary fibrosis. 
     
     
         11 . The LTBP-selective TGFβ1 inhibitor for use according to  claim 3 , wherein the muscle disease is a dystrophy, wherein optionally the dystrophy is DMD, wherein further optionally the subject is treated with a dystrophin-directed therapy. 
     
     
         12 . The LTBP-selective TGFβ1 inhibitor for use according to  claim 3 , wherein the cancer comprises a fibrotic solid tumor (e.g., desmoplasia). 
     
     
         13 . The LTBP-selective TGFβ1 inhibitor for use according to  any one of the previous claims , wherein the subject is treated with a genotoxic therapy, wherein the genotoxic therapy-induced inflammation is radiation therapy-induced inflammation or chemotherapy-induced inflammation, wherein optionally, the subject has cancer selected from:
 uterine corpus endometrial carcinoma (UCEC), thyroid carcinoma (THCA), testicular germ cell tumors (TGCT), skin cutaneous melanoma (SKCM), prostate adenocarcinoma (PRAD), ovarian serous cystadenocarcinoma (OV), lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), liver hepatocellular carcinoma (LIHC), kidney renal clear cell carcinoma (KIRC), head and neck squamous cell carcinoma (HNSC), glioblastoma multiforme (GMB), esophageal carcinoma (ESCA), colon adenocarcinoma (COAD), breast invasive carcinoma (BRCA), bladder urothelial carcinoma (BLCA), myelofibrosis, melanoma, adjuvant melanoma, renal cell carcinoma (RCC) (e.g., clear cell RCC, papillary RCC, chromophobe RCC, collecting duct RCC, and unclassified RCC), bladder cancer, colorectal cancer (CRC) (e.g., microsatellite-stable CRC, mismatch repair deficient colorectal cancer), colon cancer, rectal cancer, anal cancer, breast cancer, triple-negative breast cancer (TNBC), HER2-negative breast cancer, HER2-positive breast cancer, BRCA-mutated breast cancer, hematologic malignancies, non-small cell carcinoma, non-small cell lung cancer/carcinoma (NSCLC), small cell lung cancer/carcinoma (SCLC), extensive-stage small cell lung cancer (ES-SCLC), lymphoma (classical Hodgkin's and non-Hodgkin's), primary mediastinal large B-cell lymphoma (PMBCL), T-cell lymphoma, diffuse large B-cell lymphoma, histiocytic sarcoma, follicular dendritic cell sarcoma, interdigitating dendritic cell sarcoma, myeloma, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), small lymphocytic lymphoma (SLL), head and neck cancer (e.g., head and neck squamous cell cancer), urothelial cancer e.g., metastatic urothelial carcinoma), merkel cell carcinoma (e.g., metastatic merkel cell carcinoma), merkel cell skin cancer, cancer with high microsatellite instability (MSI-H), cancer with mismatch repair deficiency (dMMR), tumor mutation burden high cancer, mesothelioma (e.g., malignant pleural mesothelioma), gastric cancer, gastroesophageal junction cancer (GEJ), gastric adenocarcinoma, neuroendocrine tumors, gastrointestinal stromal tumors (GIST), gastric cardia adenocarcinoma, renal cancer, biliary cancer, cholangiocarcinoma, pancreatic cancer, prostate cancer, adenocarcinoma, squamous cell carcinoma, non-squamous cell carcinoma, cutaneous squamous cell carcinoma (CSCC), ovarian cancer, endometrial cancer, fallopian tube cancer, cervical cancer, peritoneal cancer, stomach cancer, brain cancers, malignant glioma, glioblastoma, gliosarcoma, neuroblastoma, thyroid cancer, adrenocortical carcinoma, oral intra-epithelial neoplasia, esophageal cancer, nasal cavity and paranasal sinus squamous cell carcinoma, nasopharynx carcinoma, salivary gland cancer, liver cancer, basal cell carcinoma, and hepatocellular cancer (HCC). 
 
     
     
         14 . The LTBP-selective TGFβ1 inhibitor for use according to  any one of the preceding claims , wherein the subject is treated with a Treg-enhancing agent, wherein optionally the Treg-enhancing agent comprises all-trans retinoic acid (ATRA), vitamin D3, indoleamine-pyrrole 2,3-dioxygenase (IDO), short-chain fatty acids (e.g., butyrate), and/or AKT/mTOR pathway inhibitors such as rapamycin. 
     
     
         15 . The LTBP-selective TGFβ1 inhibitor for use according to  any one of the preceding claims , wherein the LTBP-selective TGFβ1 inhibitor is administered in an amount sufficient to achieve a serum concentration of about 100-300 μg/mL. 
     
     
         16 . A pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof that binds recombinant human LTBP1-proTGFβ1 and/or recombinant human LTBP3-proTGFβ1 with a K D  of 10 nM or less as measured by a SPR-based assay (such as Biacore),
 wherein the antibody is not Ab42, 
 wherein the antibody competes for antigen binding with SR42 and binds an epitope comprising one or more amino acid residues of the sequence DMELVKRKRIEAIR (SEQ ID NO: 46), wherein optionally the antibody contacts one or more of the residues: Asp27 (D); Leu30 (L); Arg33 (R); Ile36 (I); Glu37 (E). 
 
     
     
         17 . A pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof that binds recombinant human LTBP1-proTGFβ1 and/or recombinant human LTBP3-proTGFβ1 with a K D  of 10 nM or less as measured by a SPR-based assay (such as Biacore),
 wherein the antibody is not Ab42; 
 wherein the antibody competes for antigen binding with SR42 and binds an epitope comprising one or more amino acid residues of the sequence YIDFRKDLGWK (SEQ ID NO: 93), wherein optionally the antibody contacts one or more of the residues: Tyr289 (Y); Lys294 (K); Asp295 (D).